Altering Neuroplasticity During Development: Impact on Substance Abuse in the Adult. This project tests the hypothesis that mechanisms of neural plasticity are key determinants of all phases of addiction, including the initial susceptibility to drug-taking behavior. Therefore, it asks whether altering neural plasticity during development will in turn alter the behavioral response to cocaine and/or its neural consequences at various stages of drug exposure. It further asks whether the impact of this developmental manipulation will be different in animals selectively bred based on the novelty-seeking trait to be either high responders (HR) or low responders (LR). This trait has been linked to differences in both initial susceptibility to self-administer drugs and differences in hippocampal neurogenesis, with the HR animals being more prone to drug-taking and showing lower rates of neurogenesis. We propose to use a developmental manipulation that enhances hippocampal neurogenesis - i.e.the neonatal administration of the Fibroblast Growth Factor 2 (FGF2). Thus, HR-bred and LR-bred animals will either receive vehicle or a small dose of FGF2 on the first day of life. They will be raised to adulthood and then exposed to cocaine either through experimenter administration or self-administration, followed by various periods of abstinence. The impact of a social stressor on their behavior and neural responses will also be tested. We hypothesize that neonatal FGF2 treatment will lead to "protection" against drug abuse both under basal and under stress conditions. We further hypothesize that the protective effect will be more marked in the novelty-seeking HR-bred animals under basal conditions, and in the LR-bred animals under stress conditions. The neural dependent variables to be tested included hippocampal morphology and rates of neurogenesis. They also include assessment of gene expression in the hippocampus and nucleus accumbens (core and shell) using a panel of genes relating to neural plasticity, including the stress, growth factor and synaptic remodeling genes studied in the other three projects. The results of this project will yield information on antecedents of drug abuse vulnerability during early development in animals with differing genetic susceptibilities to drug seeking.